1. Field of the Invention
This invention is directed to novel collagen compositions and to methods of using such compositions. In particular, the collagen compositions of this invention are directed to oxidized collagen compositions wherein the thiomethyl group of one or more of the methionine residues of the collagen has been replaced with methylsulfoxy and/or methylsulfonyl groups.
Surprisingly, the oxidized collagen compositions described herein are compatible with pharmaceutical drugs which are otherwise non-compatible with non-oxidized collagen. Accordingly, the oxidized collagen compositions described herein provide for improved drug delivery, administration, clinical utility and/or therapeutic use of certain non-compatible pharmaceutical drugs, particularly cytotoxic drugs, when used in combination with the oxidized collagen. In addition, the oxidized collagen compositions described herein will provide for improved drug delivery when used with compatible pharmaceutical drugs.
2. References
The following publications are cited in this application as superscript numbers:
1 Southard, et al., Drug Delivery Devices, U.S. Pat. No. 5,013,553 issued on May 7, 1991
2 Luck, et al., Treatments Employing Drug-Containing Matrices for Introduction into Cellular Lesion Areas, U.S. Pat. No. 4,619,913, issued Oct. 28, 1986
3 Jones, et al., Translucent Collagen Formulations with a Cytotoxic Drug, U.S. Pat. No. 5,750,146, issued May 12, 1998
All of the above references are herein incorporated by reference in their entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated herein by reference in its entirety.
3. State of the Art
Collagen is a well known biomaterial having many uses in medicine, including, for example, use as a hemostat, use in soft tissue augmentation, use for treatment of urinary incontinence, and use as a drug delivery platform. Examples of use of collagen as a drug delivery platform include collagen compositions comprising a benzo(c)phenanthridine alkaloid or a cytotoxic drug.1,2 
Collagen can be formulated with, for example, cytotoxic drugs, where the collagen is used as a drug delivery device to locally administer the drug to a patient while minimizing systemic uptake.2,3 In certain instances, the drug is compatible with the collagen for only a limited period of time and subsequently becomes non-compatible with the collagen, thereby inhibiting the effectiveness of the preparation and often adversely affecting its administration to the patient. Without being limited to any theory, it is believed that this non-compatiblity arises by undesirable reactions, such as cross-linking, between the non-compatible drug and the collagen chains. Cisplatin, for example, has a tendency to react with protein, nucleic acid, and other substances with nucleophilic groups. When cisplatin is combined into an aqueous collagen gel, the resulting preparation becomes progressively, over time, more rigid and inhomogeneous, and cisplatin recovery is decreased. It is further believed that the cisplatin reacts with nucleophilic groups in the collagen resulting in collagen cross-linking.
In affecting the ability to form physically and chemically stable collagen-based-formulations, such reactions both impair the therapeutic activity of the non-compatible pharmaceutical drug and change the rheologic characteristics of the preparation, making the material variable in efficacy and difficult to administer.
Because of this non-compatibility, it is necessary to mix cisplatin with the collagen composition just prior to administration, and to complete the administration within several hours after mixing.
In one embodiment, this invention is directed to the discovery that oxidation of the thiomethyl group in one or more methionine residues in collagen to the corresponding methylsulfoxy or methylsulfonyl group renders the resulting collagen composition more compatible with otherwise non-compatible drugs. In this regard, collagen generally exists as long, rod-shaped molecules that are comprised of a triple helix formed as either a homo- or heterottimer from three polypeptide chains. The primary structure is characterized by glycine-X—Y repeats, where a significant number of the X's are proline or hydroxyproline and Y comprises other amino acid residues, including methionine and histidine residues. At physiological pH, the individual collagen molecules self-assemble into microscopic or. macroscopic fibrils or networks, which provide the typical extracellular matrix scaffolding exhibited by collagen. When collagen is used in drug delivery applications, fibrillar collagen can act as a thickening agent in aqueous systems, providing a viscous gel-like material. Collagen can also be dried into pellet-like forms for use in sustained-release implants.
Many pharmaceutical drugs are believed to be non-compatible for use with collagen formulations because they contain functional groups that, over time, can participate in undesirable reactions with collagen, e.g., they can react with the methionine residues of collagen. These undesirable reactions can result in cross-linking between the non-compatible drug and the collagen chains. As noted above, such cross-linking significantly impairs the effectiveness of the collagen/pharmaceutical drug composition.